DESCRIPTION (Verbatim from Applicant's Abstract): Sudden cardiac death caused by ventricular fibrillation remains the major cause of human mortality. Defibrillation shock therapy is the only available treatment against ventricular fibrillation. Uncovering the mechanisms by which strong electric shocks extinguish life-threatening arrhythmias has been challenging researchers for many years. Recently, a novel concept of cardiac defibrillation termed the virtual electrode polarization hypothesis has offered a new understanding of the effects of the shock on the myocardium. Our research team has made significant contributions towards the advancement of this new concept of defibrillation. The current research project aims to further develop the virtual electrode polarization theory by taking full advantage of the combination of the state-of-the-art experimental and theoretical approaches, including in vitro fast fluorescent imaging of the rabbit heart and in numero anatomically correct active bidomain modeling of the rabbit heart. Specifically we will pursue the following aims: 1. To reconstruct the three-dimensional distribution of virtual electrode polarization in the rabbit heart during internal and external electric shocks applied during normal heartbeat and fibrillation. Areas of high transmembrane voltage gradients will be identified within the bulk of the myocardium in order to locate sites of origin of post-shock wavefronts of break-excitation. 2. To investigate the mechanisms of formation of post-shock wavefronts of re-excitation, their anatomical location, and the evolution of virtual electrode induced phase singularities into sustained scroll-waves. We will identify where and how filaments are formed within the bulk of the myocardium. 3. To develop a strategy for 'homogenization' of the virtual electrode polarization aimed at reducing the probability of scroll-wave formation, utilizing asymmetrical reversal of polarization via spatial and temporal modulation of the defibrillation field. Successful completion of this research project is likely to advance our understanding of the basic mechanisms of defibrillation and to improve efficacy and safety of implantable and external defibrillation therapy via reduction of the energy required for successful defibrillation.